Pathological changes in enteric neurons in both the small and large intestine underlie many motility disorders. Changes in nitric oxide (NO) contents of these neurons and other neighboring cells are likely to be responsible for a number of gut disorders. It is not only important to understand how enteric neural circuits are hard wired in different regions of the bowel to produce their characteristic patterns of motility but also how NO may regulate the output of enteric circuits to control propulsion. Although we are beginning to understand how enteric neurons are arranged to generate coordinated movements of the circular muscle (CM), the control and role of the longitudinal muscle (LM) is subject to much controversy. It is generally assumed that the LM and CM muscle layers are reciprocally innervated, i.e. when one contracts the other relaxes; in contrast, our recent findings suggest that both muscle layers move synchronously, contracting and relaxing together during propulsion. Also, although NO is generally believed to be an inhibitory neurotransmitter to the gut smooth muscle our preliminary findings suggest that it is also both an essential excitatory and inhibitory neuromodulator of enteric neurons in different circuits regulating peristalsis. Our preliminary observations in isolated segments of guinea-pig small and large intestine suggest that the enteric neural circuitry controlling the LM will vary in different regions of the small and large intestine; these differences probably occur owing to differences in neural projection patterns and neurochemistry which relate to function and luminal content. The long term aim of this study, therefore, is to determine the function and intrinsic neural circuitry regulating the LM, as well as the role of nitric oxide in modulating enteric neuron excitability, in three functionally different regions of isolated intestine: ileum, proximal colon and distal colon of the guinea-pig. We will use intracellular microelectrodes and tension recordings to determine the basic responses of the longitudinal and circular muscle layers to activation of ascending and descending nervous pathways by both radial and longitudinal stretch and mucosal stimulation and during peristalsis. Along with a more general pharmacological analysis, antagonists of NO synthesis and NO donors will be used to determine the role of NO in peristalsis. We will also use intracellular microelectrodes to identify the electrophysiological, morphological, and chemical coding of excitatory and inhibitory longitudinal muscle motor neurons (LMMN); the types and pharmacology of synaptic inputs and their regulation by NO; whether LMMNs are stretch sensitive and how they are activated by mucosal reflexes and during peristalsis. By analyzing the reflex pathways to the LM at the whole isolated organ level and at the individual LMMN level in these different regions of the small and large intestine we will be able to formulate important general principles regarding the intrinsic neural control of the LM in propulsion and the roles of NO in modulating peristalsis.